Polymeric compositions useful as controlled release implants

ABSTRACT

The invention is directed to an improved system for controlled release of biologically active materials and to a liquid composition for its formation. The liquid composition is composed of a thermoplastic polymer, rate modifying agent, bioactive material and organic solvent. The liquid composition is capable of forming a biodegradable and/or bioerodible microporous, solid polymer matrix. The matrix is useful as an implant in patients (humans and animals) for delivery of biologically active substances to tissues or organs.

This is a continuation of application Ser. No. 07/776,816, filed Oct.15, 1991, now abandoned.

BACKGROUND OF THE INVENTION

Biodegradable polymers are useful in many medical applications,especially drug delivery devices. Many of the biodegradable polymersused are of the thermoplastic type. Polymers made of thermoplasticresins typically liquify or soften at elevated temperatures andresolidify upon cooling. This type of polymer is generally formed intothe desired structure for use as sutures, surgical clips, staples,implants, and the like, prior to insertion into the body. Once insertedinto the body, these polymers retain their shape.

For drug delivery devices, the drug is generally incorporated into thepolymeric composition and formed into the desired shape outside thebody. This solid implant is then typically inserted into the body of ahuman, animal, bird, and the like through an incision. Alternatively,small discrete particles composed of these polymers can be injected intothe body by a syringe. Preferably, however, certain of these polymerscan be injected via syringe as a liquid polymeric composition.

Liquid polymeric compositions for use as biodegradable controlledrelease drug delivery systems are described in U.S. Pat. No. 4,938,763,issued to Dunn et al. These compositions are administered to the body ina liquid state or, alternatively, as a solution, typically via syringe.Once in the body the composition coagulates or cures into a solid. Onetype of polymeric composition consists of a nonreactive thermoplasticpolymer or copolymer dissolved in a water-miscible solvent. Thispolymeric solution is placed into the body where the polymer congeals orprecipitatively solidifies upon the dissipation or diffusion of thesolvent into the surrounding body tissues.

The presence of a plasticizer within a sustained release composition isknown to advance or speed up the release of bioactive material by thesustained release polymer. Known plasticizers have been used to enhancethe delivery of drugs from diffusional therapeutic systems. For example,K. Juni et al., Chem. Pharm. Bull., 33, 1609 (1985) disclose that therelease rate of bleomycin from polylactic acid microspheres is greatlyenhanced by incorporating fatty acid esters into the microspheres. U.S.Pat. No. 4,127,127, issued to Wong et al., discloses systems made fromfilms of segmented copolyesters of butylene terephthalate andpolyalkylene ether terephthalate that incorporate plasticizers to createa more diffusible system. Water-insoluble liquid plasticizers are usedto "soften" the copolyester and cause its diffusion coefficient toincrease, thereby enhancing the diffusion of nonionic drugs.Water-soluble plasticizers are used to create a water-swollenmicroporous structure, by leaching slowly from the copolyester, to makethe composition more permeable to drugs.

Although the liquid polymeric systems as described by Dunn et al. haveproven to be beneficial in many respects, they do not enable variablecontrol of release rate, especially control such that the rate isslower. Consequently, there is the need for a liquid composition inwhich the rate of drug delivery can be more readily controlledespecially for a drug that requires longer term release.

It is, therefore, an object of the present invention to provide animproved composition comprising a biodegradable or bioerodible polymerfor use as an implant in the body of a human, bird, fish, etc. Anotherobject is to provide an improved polymeric composition for a diffusionaltherapeutic delivery system that can be administered to an implant sitein liquid form. Yet another object is to provide an improved polymericcomposition that forms a solid matrix in situ thereby forming an implantfor sustained release of a medicament over a desired period of time. Afurther object is to provide a liquid or solution polymeric compositionthat can form in situ a biodegradable solid or gelatinous drug deliverysystem wherein the amount and rate of the material delivered can becontrolled, more precisely, especially when long-term release isrequired.

SUMMARY OF THE INVENTION

The present invention is directed to a polymer system, a method fortherapeutic treatment using the polymer system, and a precursor of thepolymer system, a liquid composition.

The polymer system is a microporous, solid matrix of a biocompatible,biodegradable thermoplastic polymer, a rate modifying agent and abioactive material. The system displays control of the rate and extentof release of the bioactive agent from the matrix. As used herein, theterm "biologically active material" or "bioactive material" means adrug, medicament, or some other substance capable of producing an effecton a body, e.g., a mammal.

The liquid composition is a combination of an organic solvent, thebiocompatible, biodegradable thermoplastic polymer, the rate modifyingagent and the bioactive material.

The polymer system is formed by applying the liquid composition to anaqueous medium that is internal (body fluids) or external to the body.After application, the liquid composition coagulates to form the polymersystem. Administration of the liquid composition directly into the bodyforms in situ the polymer system. External addition of the liquidcomposition to an aqueous liquid forms the polymer system outside thebody. The solid implantable polymer system can then be surgically placedinto the body. In all embodiments and applications, the polymer systemis substantially insoluble in aqueous media.

The process by which the polymer system is formed in part is responsiblefor development of the rate and release control. Interaction of theliquid composition with an aqueous medium either in situ in the body orexternal to the body to coagulate the composition into the polymersystem at least in part causes the desired controlled release profile asa function of the variation of the below-mentioned parameters andcomponents. Simple combination of these components without passagethrough the liquid composition will not develop the controlled releaseprofile of this invention.

When the liquid composition is added to the aqueous medium, the organicsolvent diffuses into the surrounding medium (body fluids or an externalwater medium) and the polymer coagulates to form the solid matrix(polymer system). The more or less simultaneous diffusion andcoagulation produce the microporous structure of the matrix that in partis believed to be a factor in the establishment of the desired controlof rate and extent of release. Under certain conditions of theinvention, the structure exhibits a core with large pores of diametersfrom about 10 to 500 microns and a relatively nonporous skin. The skinin this preferred embodiment actually has extremely fine pores of 0.01to 0.1 microns in diameter.

Although it is not important for some uses, when the composition isplaced in the body, the resulting polymer system adopts the shape of thecavity, pocket or intercellular space into which the composition isplaced. When the polymer system is formed outside the body it can bemolded or adapted into substantially the appropriate shape of the cavityor other space of the body into which it is being fitted.

Pursuant to the parameters and conditions of the invention, the polymersystem can control the sustained release of biologically activematerials in vivo. In particular, the rate and extent of release of thebiologically active material from the polymer system of the inventionare controlled over a range of speeds and amounts. This control isaccomplished by variation of: (a) the polymer type and molecular weight,(b) the rate modifying agent, (c) the concentration of the polymer, (d)concentration of the biologically active material, (e) the form of thebiologically active material, and (f) the concentration and kinds ofother additives present, if any, within the polymer system. Preferably,the rate and extent of release of bioactive material from the polymersystem according to the invention can be controlled by varying: (1) thetype and molecular weight of the polymer or polymers, (2) theconcentration of a suitable rate modifying agent, or a mixture of ratemodifying agents and/or (3) the concentration of the polymer. Morepreferably, the control is accomplished by varying the molecular weightof the polymer and/or the concentration of the rate modifying agentpresent. Most preferably, the control is accomplished by varying boththe molecular weight of the polymer and the concentration of the ratemodifying agent. In preferred embodiments, the rate of release increasesas polymer molecular weight increases, and independent of the polymermolecular weight, the rate of release increases as the concentration ofthe rate modifying agent decreases.

The method of the invention is based upon the therapeutic effect of thein situ controlled release of the bioactive material from the polymersystem. The implantation of the liquid composition or implantation ofthe polymer system preformed as described above can generally occuranywhere within the body of a patient in need of therapeutic treatment.Examples include soft tissue such as muscle or fat; hard tissue such asbone; or a cavity or pocket such as the periodontal, oral, vaginal,rectal, nasal, or the cul-de-sac of the eye. The composition can beadministered to the implant site by any suitable method for applying aliquid, as for example, by means of a syringe, needle, cannula orcatheter. The polymer system preformed as an implant can be inserted byknown surgical techniques.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a polymer system for the controlleddelivery of bioactive materials, a liquid composition for producing sucha system, and a method for use of such a system in therapeutictreatment. The polymer system of the present invention is advantageousin that it can be manipulated to control the amount of bioactivematerial released and the rate at which it is released in vivo.

The polymer system is prepared by combining the liquid composition andan aqueous medium to coagulate the composition into a solid, microporouspolymeric matrix. The liquid composition contains a thermoplasticpolymer or copolymer in combination with a suitable solvent and ratemodifying agent. The polymers or copolymers, which form the body of thematrix, are substantially insoluble, preferably essentially completelyinsoluble, in water and body fluids. The insolubility of the matrix bodyenables it to function as a single site for the controlled release ofbioactive material. The polymers or copolymers also are biocompatibleand biodegradable and/or bioerodible within the body of an animal, e.g.,mammal. The biodegradation enables the patient to metabolize the polymermatrix so that it can be excreted by the patient without the need forfurther surgery to remove it. Because the liquid composition and polymersystem are biocompatible, the insertion process and the presence of thepolymer system within the body do not cause substantial tissueirritation or necrosis at the implant site.

The liquid composition can be administered as a liquid directly intobody tissues or cavities wherein an implant of the polymer system isformed in situ. Alternatively, the liquid composition can be externallycombined with an aqueous medium to form an implantable polymer system.The implantable polymer system is then inserted surgically into thebody.

Thermoplastic Polymer

Suitable thermoplastic polymers for incorporation as the solid matrix ofthe controlled release polymer system are solids, pharmaceuticallycompatible and biodegradable by cellular action and/or by the action ofbody fluids. Examples of appropriate thermoplastic polymers includepolylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyesteramides, polyorthoesters,polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid) polymers, polymaleic anhydrides, poly(methylvinyl)ethers, poly(amino acids), chitin, chitosan, and copolymers,terpolymers, or combinations or mixtures of the above materials.

Preferred materials are the polylactides, polyglycolides,polycaprolactones, and copolymers thereof. These polymers can be used toadvantage in the polymer system in part because they show excellentbiocompatibility. They produce little, if any, tissue irritation,inflammation, necrosis, or toxicity. In the presence of water, thesepolymers produce lactic, glycolic, and hydroxycaproic acid,respectively, which are readily metabolized by the body. Thepolylactides and polycaprolactones can also incorporate glycolidemonomer to enhance the resulting polymer's degradation.

Depending on the desired softness and flexibility of the implant rateand extent of bioactive material release, rate of degradation, and thelike, the amount and type of polymer can be varied to produce thedesired result. For example, for a relatively soft and flexible polymersystem, copolymers with a low Tg can be used, primarily thelactide/caprolactone copolymers. The ratio of glycolide to lactide or tocaprolactone can also be varied to effect water diffusibility, whichincreases with an increasing amount of the more hydrophilic monomer. Thehydrophilic character of these monomers increases in the series ascaprolactone <lactide<glycolide.

The solubility or miscibility of a thermoplastic polymer in the organicsolvent of the composition will vary according to factors such ascrystallinity, hydrophilicity, capacity for hydrogen bonding andmolecular weight of the polymer. Consequently, the molecular weight andthe concentration of the polymer in the solvent are adjusted to achievedesired miscibility, as well as a desired release rate for theincorporated bioactive material. Highly preferred thermoplastic polymersare those having solubility parameters such as a low degree ofcrystallization, a low degree of hydrogen bonding, low solubility inwater, and high solubility in organic solvents.

According to the practice of the invention, the liquid composition ofthermoplastic polymer, solvent, rate modifying agent and bioactivematerial is a stable liquid substance. Depending on the bioactivematerial and solvent chosen, either a homogenous solution of thebioactive material in organic solvent, or a suspension or dispersion ofthe bioactive material in the solvent results. In either case, thethermoplastic polymer is substantially soluble in the organic solvent.Upon placement of the liquid composition into the aqueous medium insideor outside the body, the solvent will dissipate and the polymer willsolidify to form the polymer system having the bioactive material withina solid polymeric matrix.

Organic Solvents

The solvents used in the thermoplastic compositions of the presentinvention are preferably pharmaceutically acceptable, water-miscible,and biocompatible. Preferably, they cause relatively little, if any,tissue irritation or necrosis at the site of the injection andimplantation. The solvent is water-miscible so that it will quicklydisperse from the polymeric composition into the aqueous medium such asbody fluids. Concomitant with the dispersion of solvent thethermoplastic polymer coagulates into the solid polymer system. As thethermoplastic polymer coagulates, the solvent dispersion causes poreformation within the polymer system. As a result, the liquid compositioncontaining thermoplastic polymer, solvent, rate modifying agent andbioactive substance alone will form a porous solid polymer system.

Suitable solvents include those liquid organic compounds meeting theforegoing criteria. Examples include, but are not limited to,N-methyl-2-pyrrolidone (NMP); 2-pyrrolidone (2-pyrol); C₂ -C₆ alkanols;2-ethoryethanol; alkyl esters such as 2-ethoxyethyl acetate, methylacetate, ethyl acetate, propylene carbonate, ethyl lactate; ethyleneglycol dimethyl ether; propylene glycol; alkyl ketones such as acetone,methyl ethyl ketone; dimethylformamide; dimethyl sulfoxide; dimethylsulfone; tetrahydrofuran; cyclic alkyl amides such as caprolactam;decylmethyl sulfoxide; oleic acid; N,N-dimethyl-m-toluamide; and1-dodecylazacycloheptan-2-one. The preferred solvents are,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, propylenecarbonate and ethyl lactate due, at least in part, to their solvatingability and their biocompatibility.

The solvents for the thermoplastic polymer liquid compositions of thepresent invention are chosen for compatibility and appropriatesolubility of the polymer and solvent. Lower molecular weightthermoplastic polymers will normally dissolve more readily in thesolvents than high molecular weight polymers. As a result, theconcentration of a thermoplastic polymer dissolved in the varioussolvents differs depending upon type of polymer and its molecularweight. Conversely, the higher molecular weight thermoplastic polymerswill tend to coagulate or solidify faster than the very low molecularweight thermoplastic polymers. Moreover, the higher molecular weightpolymers tend to give higher solution viscosities than the low molecularweight materials. Thus, for advantageous injection efficiency, inaddition to advantageous release rate, the molecular weight and theconcentration of the polymer in the solvent are controlled.

A solvent mixture can be used to increase the coagulation rate ofthermoplastic polymers that exhibit a slow coagulation or setting rate.In such a system one component of the mixture is typically a goodsolvent for the thermoplastic polymer, and the other component is apoorer solvent or a nonsolvent. The two liquids are mixed at a ratiosuch that the thermoplastic polymer is still soluble, but precipitateswith the slightest increase in the amount of nonsolvent, such as waterin a physiological environment. By necessity, the solvent system must bemiscible with both the thermoplastic polymer and water. An example ofsuch binary solvent system is the use of NMP and ethanol for lowmolecular weight DL-PLA. The addition of ethanol to the NMP/polymersolution increases its coagulation rate significantly.

Polymer Molecular Weight

It has been discovered that the molecular weight of the polymer used inthe present invention distinctly affects the rate of bioactive materialrelease as long as the liquid composition has been used as anintermediate. Under these conditions, as the molecular weight of thepolymer increases, the rate of bioactive material release from thesystem decreases, passes through a minimum, and then increases again.This phenomenon can be advantageously used in the formulation of systemsfor the controlled release of various bioactive materials. Forrelatively quick release of a bioactive material, polymer molecularweight on either side of the minimum for that particular polymer can bechosen to provide the desired release rate. For release of a bioactivematerial over a relatively long period of time, a polymer molecularweight in the vicinity of the minimum for the particular polymer can bechosen.

Prior to the present invention, it was known that for most, if not all,polymers, the higher the molecular weight of a polymeric composition,the slower the rate of bioactive material release. This was believed tobe a result of chain entanglements in the higher molecular weightpolymer, which were believed to slow down the diffusion of drugmolecules through the polymer matrix. In contrast, it has beensurprisingly discovered that for polymer matrices formed throughintermediacy of the liquid composition of the invention, the releaserate of a bioactive substance follows a "U" shaped curve as themolecular weight of the polymer increases. Accordingly, a polymer systemcan be produced with an optimum polymer molecular weight range for therelease of bioactive substances over a selected length of time.

For the polymer system of the present invention, the typical minimumrate of release of the incorporated bioactive material occurs at aninherent viscosity (I.V. in deciliters/gm) of about 0.2 but can varydepending on the particular components of the composition. For mostsystems it is preferred to adjust the molecular weight of the polymer toat least about 0.2 I.V. (15,000 molecular weight as determined by gelpermeation chromatography in comparison to polystyrene) for a moresustained release of the bioactive material. Typically, acceptablesustained release rates are obtained if the molecular weight is belowabout 0.8 I.V. (100,000 molecular weight). More preferably, themolecular weight is adjusted to be within a range of about 0.2-0.5 I.V.,for effective sustained release. For a poly(DL-lactide) or alactide-co-glycolide system, as discussed below, the desired molecularweight range is about 0.2-0.5 I.V. If a molecular weight of a specificpolymer is chosen from these parameters and the release of the bioactivesubstance is too slow or too fast, the rate can be varied simply bydetermining a few experimental points along the U curve for that polymerand adjusting the molecular weight accordingly.

The molecular weight of a polymer can be varied by any of a variety ofmethods. The choice of method is typically determined by the type ofpolymer composition. For example, if a thermoplastic polymer is usedthat is biodegradable by hydrolysis, the molecular weight can be variedby controlled hydrolysis, such as in a steam autoclave. Typically, thedegree of polymerization can be controlled, for example, by varying thenumber and type of reactive groups and the reaction times.

Rate Modifying Agents

It has been discovered that under the conditions of the invention, ratemodifying agents provide significantly improved control to the sustainedrelease character of the polymer system of the present invention. Thecombination of a rate modifying agent and matrix polymer as influencedby the interaction of the liquid composition with an aqueous mediumaccording to the present invention has the surprising effect ofretarding the release of the bioactive material. This effect contrastswith the knowledge and belief in the art. Under typical, knowncircumstances, which do not result from the interaction of the liquidcomposition and an aqueous medium, use of a rate modifying agent withina sustained release matrix will only increase the rate of release of thepharmaceutical compound within the matrix. Thus, under most knowncircumstances, it is difficult, if not impossible, to slow down orretard the release of a medicament from an implant.

As practiced according to the present invention, the use of a ratemodifying agent in the polymer system of the present invention can beadapted to cause a decrease in the range of multiple orders of magnitude(e.g., 1 to 10 to 100), preferably up to a ten-fold decrease, in therelease rate of the bioactive material relative to that of the samepolymer matrix without the rate modifying agent. For example, naltrexoneand doxycycline are substantially completely released from a polymermatrix of poly(DL-lactide) within about two to three days in vitro. Withthe addition of a rate modifying agent (e.g., ethyl heptanoate) andformation of the polymer system through interaction of the liquidcomposition and an aqueous medium, the release rate can be slowed toproduce substantially complete release of the drug within about sevendays. With the use of a greater amount of rate modifying agent accordingto the invention, the period of time can be increased to about fourteendays. By appropriate choice of the polymer molecular weight in optionalcombination (i.e., from none to significant proportions) with the ratemodifying agent, the rate and extent of bioactive material release fromthe polymer system can be varied from very fast to very slow.

Rate modifying agents useful in the invention are typically misciblewith the polymer. That is, the rate modifying agent and polymer arechosen for a particular composition such that the intermolecular forcesof each are similar. Rate modifying agents can be either water-solubleor water-insoluble. Preferably, they are water-insoluble, i.e.,immiscible. The specific rate modifying agent chosen for a polymersystem is preferably more hydrophobic than the organic solvent of choicefor that polymer system. It is also preferably a high boiling liquid.

Although it is not intended to be a limitation of the invention, it isbelieved the rate modifying agent affects the release rate of thepolymer system of the present invention by causing the formation of aheretofore unknown distinctive macromolecular structure within the skinand core of the implant as the implant is formed. The distinctivestructure is believed to slow down the cross-diffusion of bioactivematerial and body fluid. It is believed to be absent from implantsformed without rate modifying agent or those containing rate modifyingagent but which are not prepared through the intermediacy of the liquidcomposition. Irrespective of the mechanism of action, the effectcontrols the release characteristics of the polymer system of theinvention.

The rate modifying agent chosen typically imparts to an implant a glasstransition temperature (Tg) of less than about 55° C., preferably lessthan about 50° C., and more preferably less than about 37° C. such thatthe implant is soft, resilient, and flexible in the body.

The rate modifying agents used in the present invention arepharmaceutically acceptable. Typically, the rate modifiers are organiccompounds that substitute as the complementary molecules for secondaryvalence bonding that typically occurs between polymer molecules. Suchcompounds increase the flexibility and ability of the polymer moleculesto slide past each other. The chemical formulas of such compounds willexhibit hydrophobic and hydrophilic regions so as to effect secondaryvalence bonding. Such organic compounds are often characterized as"plasticizers". However, typical "plasticizers" are not the onlycompounds that function as rate modifying agents in the polymer systemof the present invention to control the rate of release of a bioactivematerial. Other useful rate modifying agents include fatty acids,triglycerides, other hydrophobic compounds and some organic solvents.

Specific examples of rate modifying agents include, but are not limitedto esters of mono-, di-, and tricarboxylic acids, such as 2-ethoxyethylacetate, methyl acetate, ethyl acetate, diethyl phthalate, dimethylphthalate, dibutyl phthalate, dimethyl adipate, dimethyl succinate,dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributylcitrate, acetyl triethyl citrate, glycerol triacetate, di(n-butyl)sebecate, and the like; polyhydroxy alcohols, such as propylene glycol,polyethylene glycol, glycerin, sorbitol, and the like; fatty acids;triesters of glycerol, such as triglycerides, epoxidized soybean oil,and other epoxidized vegetable oils; sterols, such as cholesterol;alcohols, such as C₆ -C₁₂ alkanols, 2-ethoxyethanol, and the like.Mixtures of rate modifying agents, such as glycerin/propylene glycol,sorbitol/glycerine, ethylene oxide/propylene oxide, and butyleneglycol/adipic acid, can also be used in the polymer systems of theinvention.

The choice of rate modifying agent employed depends on the mixture ofpolymers and the solvent in the thermoplastic system. Preferred ratemodifying agents include dimethyl citrate, triethyl citrate, ethylheptanoate, glycerin, and hexanediol.

The quantity of rate modifying agent in the system will vary dependingon the release rate of the medicament desired. Typically, the ratemodifying agent is present in an amount up to about 15%, preferably upto about 10%, based upon the total weight of the system.

Polymer Concentration

The concentration of the polymer in the system can also be varied toadjust the release rate of the incorporated bioactive material. It hasbeen discovered that the more dilute the polymer concentration, the morereadily the bioactive material will be released. For example, in asystem containing 5 percent flurbiprofen and a polymer concentration of55 percent poly(DL-lactide), a cumulative release of approximately 11.4percent at day 1 and 23 percent at day 7 is seen. With a polymerconcentration of 45 percent, the cumulative percent release at day 1 is23 percent and about 40 percent at day 7.

This effect can be used in combination with other methods to moreeffectively control the release of the incorporated medicament asdesired. For example, by adjusting the concentration of the polymer, andbioactive material if desired, along with the control of the molecularweight and the amount of rate modifying agent, a wide range of releaserates can be obtained.

Pore-Forming Agents

Other additives can be used to advantage in further controlling thedesired release rate of a bioactive material for a particular treatmentprotocol. For example, if the thermoplastic polymer liquid compositionis too impervious to water, a pore-forming agent can be added togenerate additional pores in the matrix. Any biocompatible water-solublematerial can be used as the pore-forming agent. These agents can beeither soluble in the liquid composition or simply dispersed within it.They are capable of dissolving, diffusing or dispersing out of both thecoagulating polymer matrix and the formed polymer system whereupon poresand microporous channels are generated in the matrix and system. Theamount of pore-forming agent (and size of dispersed particles of suchpore-forming agent, if appropriate) within the composition will directlyaffect the size and number of the pores in the polymer system.

Other factors can also influence the size and/or diameter of the poresformed in the polymer system. For example, the amount of organicsolvent, and the rate at which the polymer system solidifies, can allaffect the porosity of the polymer system. Although a generallymicroporous matrix without a resolved core and skin can be producedaccording to the invention, typically, without an additionalpore-forming agent a polymer system formed from the liquid compositionis composed of a surface skin and inner core. The surface skin istypically less porous, and even relatively nonporous, when compared tothe inner core. The inner core can contain pores with a diameter ofabout 10-1000 um. With additional pore-forming agent, the pore sizes ofthe core and skin become substantially uniform such that they both havepores in the range of 10 to 1000

The concentration of pore-forming agent relative to thermoplasticpolymer in the composition will vary according to the degree ofpore-formation desired. Generally, this concentration will range fromabout 0.01 to 1 gram of pore-forming agent per gram of polymer. If theagent is soluble in the liquid composition, then the mixing ordistribution of the agent in the liquid composition and the aggregationwhen the thermoplastic coagulates will determine the size of theresultant pores as the agent dissolves out of the polymer matrix.

Pore-forming agents include, any pharmaceutically acceptable organic orinorganic substance that is substantially miscible in water and bodyfluids and will dissipate from the forming and formed matrix intoaqueous medium or body fluids or water-immiscible substances thatrapidly degrade to water-soluble substances. The pore-forming agent maybe soluble or insoluble in the polymer liquid composition of theinvention. In the liquid composition of the invention, it is furtherpreferred that the pore-forming agent is miscible or dispersible in theorganic solvent to form a uniform mixture. Suitable pore-forming agentsinclude, for example, sugars such as sucrose and dextrose, salts such assodium chloride and sodium carbonate, and polymers such ashydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol,and polyvinylpyrrolidone. The size and extent of the pores can be variedover a wide range by changing the molecular weight and percentage ofpore-forming agent incorporated into the polymer system.

Bioactive Materials

The terms "drug," "medicament," or "bioactive material" (i.e.,biologically active material) as used herein include, biologically,physiologically, or pharmacologically active substances that act locallyor systemically in the human or animal body. Various forms of themedicaments or biologically active materials can be used which arecapable of being released from the polymer matrix into adjacent tissuesor fluids. The medicaments are at least very slightly water-soluble,preferably moderately water-soluble, and are diffusible through thepolymeric composition. They can be acidic, basic, or salts. They can beneutral molecules, polar molecules, or molecular complexes capable ofhydrogen bonding. They can be in the form of ethers, esters, amides andthe like, which are biologically activated when injected into the humanor animal body.

Generally, any drugs or bioactive materials that can be dissolved ordispersed in an aqueous environment can be utilized in the liquidcomposition and polymer system of the present invention. For example,the bioactive material can be a penicillin or cephalosporin antibiotic,a hormone such as ACTH, estrogen or testosterone, a protein such as amonoclonal antibody or an essential human or animal enzyme, insulin oran insulin precursor, a vaccine or serum substance useful in thetreatment of viral diseases, an activator or inhibitor of a specificenzyme, a releasing factor for a physiologically active substance, orany other suitable substance.

Representative drugs or bioactive materials that can be used in theinjectable sustained release compositions of the present inventioninclude, but are not limited to, peptide drugs, protein drugs, such asenzymes, insulin, interleukin, platelet anticoagulating agent, hormones,calcitonin, vasopressin, desensitizing agents, bronchodilating agents,anti-infective agents, antibiotics, antimicrobial agents,anti-allergenics, androgenic steroids, decongestants, hypnotics,steroidal and nonsteroidal anti-inflammatory agents, anticholinergics,sympathomimetics, sedatives, miotics, steroids, corticosteroids,regulatory agents, nephritic agents, psychic energizers, tranquilizers,vaccines, estrogens, progestational agents, humoral agents,prostaglandins, analgesics, antispasmodics, antimalarials,antihistamines, cardioactive agents, male and female birth controlagents, tissue growth factors, antiparkinsonian agents, antihypertensiveagents, α-adrenergic blocking agents, nutritional agents, and alkaloidpharmaceutical agents.

The bioactive material may also be a substance, or metabolic precursorthereof, which is capable of promoting growth and survival of cells andtissues, or augmenting the activity of functioning cells, as forexample, blood cells, neurons, muscle, bone marrow, bone cells andtissues, and the like. For example, the bioactive material may be anerve growth promoting substance, as for example, a ganglioside,phosphatidylserine, a nerve growth factor, brain-derived neurotrophicfactor, a fibroblast growth factor, and the like. In particular, the insitu implants are capable of enhancing regeneration of the perlodontiumby providing an outer surface having a porosity which serves as aphysical barrier between an exposed root surface and encroachingepithelial cells to promote guided tissue regeneration.

To promote tissue growth, the biologically active material may be atissue growth factor substance. Suitable tissue growth promoting agentsinclude, for example, fibronectin (FN), endothelial cell growth factor(ECGF), cementum attachment extracts (CAE), human growth hormone (HGH),a periodontal ligament cell growth factor, animal growth hormones,fibrobiast growth factor (FGF), platelet derived growth factor (PDGF),epidermal growth factor (EGF), protein growth factor, interleukin-1(IL-1), transforming growth factor (TGF-α or TGF-β), insulin-like growthfactor II (IGF-II), human alpha thrombin (HAT), osteoinductive factor(OIF), bone morphogenetic protein (BMP) or protein derived therefrom,demineralized bone matrix, and releasing factors thereof. Further, theagent may be a bone growth promoting substance such as hydroxyapatite,tricalcium phosphate, a di- or polyphosphonic acid, an anti-estrogen, asodium fluoride preparation, a substance having a phosphate to calciumratio similar to natural bone, and the like. A bone growth promotingsubstance may be in the form, as for example, of bone chips, bonecrystals or mineral fractions of bone and/or teeth, a synthetichydroxyapatite, or other suitable form. The agent may further be capableof treating metabolic bone disorders such as abnormal calcium andphosphate metabolism, by for example, inhibiting bone resorption,promoting bone mineralization, or inhibiting calcification.

The bioactive material can be miscible in the polymer and/or solvent toprovide a homogenous mixture with the polymer, or insoluble in thepolymer and/or solvent to form a suspension or dispersion with thepolymer.

Upon formation of the polymer system from the liquid composition, thebiologically active material becomes incorporated into the polymermatrix. After implantation of the externally formed polymer system orinsertion of the liquid composition to form in situ the polymer system,the bioactive material will be released from the matrix into theadjacent tissues or fluids by diffusion and polymer degradationmechanisms. Manipulation of these mechanisms also can influence therelease of the bioactive material into the surroundings at a controlledrate. For example, the polymer matrix can be formulated to degrade afteran effective an/or substantial amount of the bioactive material isreleased from the matrix. Release of a material having a low solubilityin water, as for example a peptide or protein, typically requires thedegradation of a substantial part of the polymer matrix to expose thematerial directly to the surrounding tissue fluids. Thus, the release ofthe biologically active material from the matrix can be varied by, forexample, the solubility of the bioactive material in water, thedistribution of the bioactive material within the matrix, or the size,shape, porosity, solubility and biodegradability of the polymer matrix,among other factors. The release of the biologically active materialfrom the matrix is controlled relative to its intrinsic rate by varyingthe polymer molecular weight and by adding a rate modifying agent toprovide a desired duration and rate of release, as described above.

The polymer system is formulated to contain the bioactive material in anamount effective to provide a desired biological, physiological and/ortherapeutic effect. The "effective amount" of a biologically activematerial incorporated into the injectable polymeric composition of theinvention depends on a variety of factors, such as the desired releaseprofile, the concentration of bioactive material required for a desiredbiological effect, and the period of time over which the bioactivematerial needs to be released for desired treatment. Ultimately, thisamount is determined by the human or animal patient's physician orveterinarian, respectively, who will apply his experience and wisdom inprescribing the appropriate kind and amount of bioactive material toprovide therapy for the patient. There is generally no critical upperlimit on the amount of bioactive material incorporated into the polymersolution. The only limitation is a physical limitation for advantageousapplication, i.e., the bioactive material should not be present in sucha high concentration that the solution or dispersion viscosity is toohigh for injection. The lower limit of bioactive material incorporatedinto the polymer system typically depends only on the activity of thebioactive material and the period of time desired for treatment.

Administration of the liquid composition or the externally formedpolymer system of the invention ultimately will be accomplishedaccording to the wisdom and protocol of the patient's attending healthcare professional such as a physician, or if appropriate, a dentist orDVM. Choice of the particular composition will depend upon the conditionto be treated, which choice will be made by the attending health careprofessional. When the liquid composition is injected into soft tissueto provide a sustained release implant, the resulting polymer systemwill both release the bioactive material and biodegrade as designed sothat no residue remains. When the liquid composition is injected into asoft tissue defect and a suitable bioactive material for assisting incollagen formation is in the composition, the resulting polymer systemfills the defect and provides a support structure upon which naturalcollagen tissue can grow. This collagen tissue gradually replaces thebiodegradable polymer. With hard tissue such as bone, the biodegradablepolymer containing a bone growth factor supports the growth of new bonecells. These new bone cells eventually replace the degrading polymer.

The following examples are set forth as representative specific andpreferred embodiments of the present invention. These examples are notto be construed as limiting the scope of the invention in any manner. Itshould be understood that many variations and modifications can be madewhile remaining within the spirit and scope of the invention.

EXAMPLE 1 Effect of Rate Modifying Agent

Formulations were prepared with poly(DL-lactide), N-methylpyrrolidone,and naltrexone hydrochloride (3.0%). The formulations differed in theamount of ethyl heptanoate (rate modifying agent). Release was into pH7.2 phosphate buffered saline (PBS). The polymer formulation wasprecipitated into the PBS by expelling it from a 1 mL syringe. The PBSsolutions were placed in a 37° C. shaker bath. At regular intervals thePBS solution was removed, and replaced with fresh PBS. The PBS solutionswere analyzed by UV absorption at 285 nm to determine naltrexonehydrochloride concentration. The cumulative percent released istabulated in Table 1.

                  TABLE 1                                                         ______________________________________                                        EFFECT OF RATE MODIFYING AGENT CONTENT ON RELEASE                             OF NALTREXONE HYDROCHLORIDE                                                   Day      0%            5%     10%                                             ______________________________________                                        1        71.3          27.6    5.7                                            2        85.2          32.9   10.0                                            4        96.4          41.2   15.5                                            7        97.4          44.6   15.5                                            10       100.8         49.2   17.7                                            17       101.8         --     --                                              20       --            64.7   33.6                                            ______________________________________                                    

EXAMPLE 2 Effect of Rate Modifying Agent with Doxycycline Hyclate

Formulations were prepared with poly(DL-lactide),N-methyl-2-pyrrolidone, and 5% doxycycline hyclate. One formulationcontained 5% ethyl heptanoate as a rate modifying agent and the otherformulation served as a control with no ethyl heptanoate being present.Release of doxycycline from the formulations and analysis of the releaserates were performed as described in Example 1 except a pH 6.85phosphate buffered saline was used. The cumulative percent released istabulated in Table 2.

                  TABLE 2                                                         ______________________________________                                        EFFECT OF RATE MODIFYING AGENT CONTENT ON                                     RELEASE OF DOXYCYCLINE HYCLATE                                                Day              0%     5%                                                    ______________________________________                                        1                23.2   1.6                                                   8                64.0   3.0                                                   23               71.9   6.3                                                   ______________________________________                                    

EXAMPLE 3 Effect of Molecular Weight with Poly(DL-lactide-co-glycolide)

Formulations were prepared using various molecular weights of 50:50poly(DL-lactide-co-glycolide) (PLG). The molecular weights of thepolymers were estimated by an inherent viscosity (I.V.) measurement inchloroform, with lower I.V. values corresponding to lower molecularweights. The formulations were prepared by dissolving the polymer inN-methyl-2-pyrrolidone (NMP) to give a 50% solution. To this solutionwas added naltrexone free base to give a formulation with the overallcomposition of 5% naltrexone free base, 47.5% PLG and 47.5% NMP.

A controlled size drop of formulation was expelled from a 1 mL syringeinto pH 7.4 phosphate buffered saline (PBS). The PBS was maintained at37° C. with agitation. At regular intervals the PBS was removed andreplaced with fresh PBS. The release solutions removed were analyzed fornaltrexone content by high performance liquid chromatography (HPLC).Cumulative percent release data are presented in Table 3.

                  TABLE 3                                                         ______________________________________                                        EFFECT OF MOLECULAR WEIGHT ON RELEASE                                         OF NALTREXONE FREE BASE FROM 50:50                                            POLY (DL-LACTIDE-CO-GLYCOLIDE)                                                (Polymer I.V.)                                                                Day    0.19       0.35   0.52    0.61 0.73                                    ______________________________________                                        1      10.2       7.6    9.2     27.5 46.7                                    2      25.0       10.9   11.2    33.3 55.5                                    4      36.3       16.2   14.9    39.9 68.0                                    7      43.5       26.5   21.5    45.0 73.6                                    10     54.7       34.6   31.9    56.4 77.8                                    ______________________________________                                    

EXAMPLE 4 Effect of Molecular Weight with Poly(DL-lactide)

Formulations were prepared with 10% naloxone hydrochloride, 45%poly(DL-lactide) (PLA) and 45% NMP. In this trial, three molecularweights of PLA were used. The lower and higher I.V. polymers wereobtained from commercial sources whereas the intermediate molecularweight polymer (I.V.=0.21) was prepared by autoclaving a highermolecular weight PLA. Release of naloxone from the formulations andanalysis of the release rates were performed as described in Example 1,except for the naloxone content being determined by ultravioletspectroscopy (UV) instead of HPLC. Cumulative percent release data arepresented in Table 4.

                  TABLE 4                                                         ______________________________________                                        EFFECT OF MOLECULAR WEIGHT ON RELEASE OF                                      NALOXONE HYDROCHLORIDE FROM POLY(DL-LACTIDE)                                         (Polyiner I.V.)                                                        Hours    0.11           0.21   0.33                                           ______________________________________                                        3        72.6           17.2   29.6                                           6        76.9           29.7   40.0                                           12       80.4           43.7   52.6                                           24       86.9           54.4   69.7                                           48       98.6           59.3   82.4                                           96       101.3          62.7   90.5                                           ______________________________________                                    

EXAMPLE 5 Polymer Autoclaving

Because poly(DL-lactide) is degradable by hydrolysis, lower molecularweight samples can be prepared by reacting a higher molecular weightpolymer sample with water. This is most conveniently done in acontrolled manner in a steam autoclave.

The polymer, in powdered form, is spread thinly in a teflon-lined glasspetri dish. The polymer is placed in a steam autoclave at 22 psi. Thetime the polymer is allowed to remain in the autoclave determines thefinal molecular weight (longer times=lower molecular weight). Thedecision on the amount of time is semi-empirical at best. The polymer isremoved from the autoclave, cooled and dried in vacuo. The dried polymercan be purified by dissolving it in methylene chloride, andprecipitating the resulting solution in methanol.

After complete drying in vacuo, the polymer molecular weight can bedetermined by gel permeation chromatography (GPC), or estimated byinherent viscosity. The monomer ratio can be determined by nuclearmagnetic resonance (NMR).

What is claimed is:
 1. A thermoplastic polymer system suitable as acontrolled release implant, comprising:a solid, microporous matrix of apharmaceutically acceptable, biodegradable thermoplastic polymer whichis insoluble in aqueous medium or human or animal body fluids, abiologically active agent, and up to about 15% by weight of apharmaceutically acceptable, water-insoluble, rate-retarding agent whichretards the rate of release of the biologically active agent from thematrix up to 100 fold relative to its rate of release from the samematrix without the rate-retarding agent, and which imparts a Tg to thematrix of less than about 55° C., the weight being relative to the totalweight of the matrix; and, the microporous matrix being formedexternally or in situ respectively by a process comprising combining acomposition with the aqueous medium, or administering the compositiondirectly into a body tissue or cavity having the human or animal bodyfluids; the composition comprising the thermoplastic polymer, thebiologically active agent, the rate-retarding agent and apharmaceutically acceptable organic solvent in which the thermoplasticpolymer, biologically active agent and rate-retarding agent aredissolved or dispersed, the organic solvent being miscible todispersible in aqueous medium or human or animal body fluids; thecombining step or administering step resulting in diffusion of theorganic solvent into the aqueous medium or body fluid and resulting incoagulation of the thermoplastic polymer to form the solid microporousmatrix; the thermoplastic polymer being selected from the groupconsisting of polylactides, polyglycolides, polycaprolactones,polyanhydrides, polyamides, polyurethanes, polyesteramides,polyothoesters, polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid), poly(amino acids), and copolymers, terpolymers and anycombination thereof, and the thermoplastic polymer having a molecularweight up to about 0.8 inherent viscosity; and, the rate-retarding agentbeing selected from the group consisting of an ester of a mono, di ortricarboxylic acid, a polyhydroxy alcohol, a fatty acid, a fatty acidester, an epoxidized oil, a sterol, a higher alkyl alcohol, and anymixture thereof.
 2. A system according to claim 1 wherein therate-retarding agent is less water-soluble than the organic solvent. 3.A system according to claim 1 wherein the solvent is selected form thegroup consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol,propylene glycol, acetone, acetic acid, ethyl acetate, ethyl lactate,methyl acetate, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide, dimethyl sulfone, tetrahydrofuran, propylene carbonate,caprolactam, decylmethylsulfoxide, oleic acid, N,N-diethyl-m-toluamide,and t-dodecylazacycloheptan-2-one, and any combination thereof.
 4. Asystem according to claim 1 wherein the rate-retarding agent is selectedfrom the group consisting of ethyl heptanoate, glycerin, diethylcitrate, and triethyl citrate.
 5. A system according to claim 1 furthercomprising a pore forming agent.
 6. A system according to claim 1wherein the matrix comprises a core and skin, the core being microporousand the skin having pores of substantially smaller size than the core.7. A system according to claim 1 wherein the thermoplastic polymer ispolylactide, polyglycolide, polycaprolactone or a copolymer of anycombination of lactide, glycolide and caprolactone monomer.
 8. Acomposition suitable for formation of a controlled release implant foruse in a patient, comprising:a) a pharmaceutically acceptable,biodegradable thermoplastic polymer that is insoluble in aqueous mediumor human or animal body fluid; b) a biocompatible organic solvent thatis miscible to dispersible in water or human or animal body fluids; c) abiologically active compound; d) up to about 15% by weight of apharmaceutically acceptable, water-insoluble, rate-retarding agent whichremains in the implant after the formation of the implant from thecomposition, which imparts a Tg to the implant of less than about 55°C., and which retards the rate of release of the biologically activecompound from the implant up to 100 fold relative to the rate of releaseof the biologically active compound from the same implant without therate-retarding agent when the implant is made externally or in siturespectively by combining the composition and the aqueous medium or byadministering the composition directly to a body tissue or cavity havingthe human or animal body fluids, the weight being relative to the sum ofthe weights of the thermoplastic polymer, the biologically active agentand the rate retarding-agent: the combining step or administering stepresulting in diffusion of the organic solvent into the aqueous medium orbody fluid and resulting in coagulation of the thermoplastic polymer toform the solid microporous matrix: the thermoplastic polymer beingselected from the group consisting of polylactides, polyglycolides,polycaprolactones, polyanhydrides, polyamides, polyurethanes,polyesteramides, polyothoesters, polydioxanones, polyacetals,polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), poly(amino acids), andcopolymers, terpolymers and any combination thereof and thethermoplastic polymer having a molecular weight up to about 0.8 inherentviscosity; and, the rate-retarding agent being selected from the groupconsisting of an ester of a mono, di or tricarboxylic acid, apolyhydroxy alcohol, a fatty acid, a fatty, acid ester, an epoxidizedoil, a sterol, a higher alkyl alcohol, and any mixture thereof.